SummaryThe main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.

The main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.

Max ERC Funding

1 000 000 €

Duration

Start date: 2008-11-01, End date: 2014-10-31

Project acronymAGALT

ProjectAsymptotic Geometric Analysis and Learning Theory

Researcher (PI)Shahar Mendelson

Host Institution (HI)TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY

Call DetailsStarting Grant (StG), PE1, ERC-2007-StG

SummaryIn a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

Max ERC Funding

750 000 €

Duration

Start date: 2009-03-01, End date: 2014-02-28

Project acronymAIDA

ProjectArchitectural design In Dialogue with dis-Ability Theoretical and methodological exploration of a multi-sensorial design approach in architecture

Researcher (PI)Ann Heylighen

Host Institution (HI)KATHOLIEKE UNIVERSITEIT LEUVEN

Call DetailsStarting Grant (StG), SH2, ERC-2007-StG

SummaryThis research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.

This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.

SummaryAnxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.

Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.

Max ERC Funding

812 986 €

Duration

Start date: 2008-11-01, End date: 2013-10-31

Project acronymBACTERIAL SPORES

ProjectInvestigating the Nature of Bacterial Spores

Researcher (PI)Sigal Ben-Yehuda

Host Institution (HI)THE HEBREW UNIVERSITY OF JERUSALEM

Call DetailsStarting Grant (StG), LS3, ERC-2007-StG

SummaryWhen triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.

When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.

SummaryThe overall objective of the proposal is to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in vivo and, secondly, study the role of multivalency and spatial organization in carbohydrate recognition. Both of these projects exploit the programmable pre-organization of peptide nucleic acid (PNA) to induce a chemical reaction in the first case or modulate a ligand-receptor interaction in the second case. For nucleic acid detection, a DNA or RNA fragment will be utilized to bring two PNA fragments bearing reactive functionalities in close proximity thereby promoting a reaction. Two types of reactions are proposed, the first one to release a fluorophore for imaging purposes and the second one to release a drug as an “intelligent” therapeutic. If affinities are programmed such that hybridization is reversible, the template can work catalytically leading to large amplifications. As a proof of concept, this method will be used to measure the transcription level of genes implicated in stem cell differentiation and detect mutations in oncogenes. For the purpose of studying multivalent carbohydrate ligand architectures, the challenge of chemical synthesis has been a limiting factor. A supramolecular approach is proposed herein where different arrangements of carbohydrates can be displayed in a well organized fashion by hybridizing PNA-tagged carbohydrates to DNA templates. This will be used not only to control the distance between multiple ligands or to create combinatorial arrangements of hetero ligands but also to access more complex architectures such as Hollyday junctions. The oligosaccharide units will be prepared using de novo organoctalytic reactions. This technology will be first applied to probe the recognition events between HIV and dendritic cells which promote HIV infection.

The overall objective of the proposal is to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in vivo and, secondly, study the role of multivalency and spatial organization in carbohydrate recognition. Both of these projects exploit the programmable pre-organization of peptide nucleic acid (PNA) to induce a chemical reaction in the first case or modulate a ligand-receptor interaction in the second case. For nucleic acid detection, a DNA or RNA fragment will be utilized to bring two PNA fragments bearing reactive functionalities in close proximity thereby promoting a reaction. Two types of reactions are proposed, the first one to release a fluorophore for imaging purposes and the second one to release a drug as an “intelligent” therapeutic. If affinities are programmed such that hybridization is reversible, the template can work catalytically leading to large amplifications. As a proof of concept, this method will be used to measure the transcription level of genes implicated in stem cell differentiation and detect mutations in oncogenes. For the purpose of studying multivalent carbohydrate ligand architectures, the challenge of chemical synthesis has been a limiting factor. A supramolecular approach is proposed herein where different arrangements of carbohydrates can be displayed in a well organized fashion by hybridizing PNA-tagged carbohydrates to DNA templates. This will be used not only to control the distance between multiple ligands or to create combinatorial arrangements of hetero ligands but also to access more complex architectures such as Hollyday junctions. The oligosaccharide units will be prepared using de novo organoctalytic reactions. This technology will be first applied to probe the recognition events between HIV and dendritic cells which promote HIV infection.

SummaryThis project will focus on the use of nanoporous metal organic frameworks (Fe, Zn, Ti) for bioapplications. These systems are exciting porous solids, built up from inorganic clusters and polycarboxylates. This results in open-framework solids with different pore shapes and dimensions, and applications such as catalysis, separation and storage of gases. I have recently initiated the synthesis of new trivalent transition metal carboxylates. Among them, the metal carboxylates MIL-100 and MIL-101 (MIL: Materials of Institut Lavoisier) are spectacular solids with giant pores (25-34 Å), accessible metal sites and huge surface areas (3100-5900 m2.g-1). Recently, it was shown that these solids could be used for drug delivery with a loading of 1.4 g of Ibuprofen per gram of MIL-101 solid and a total release in six days. This project will concentrate on the implication of MOFs for drug release and other bioapplications. Whereas research on drug delivery is currently focused either on the use of bio-compatible polymers or mesoporous materials, our method will combine advantages of both routes including a high loading and a slow release of therapeutic molecules. A second application will use solids with accessible metal sites to coordinate NO for its controlled delivery. This would provide exogenous NO for prophylactic and therapeutic processes, anti-thrombogenic medical devices, improved dressings for wounds and ulcers, and the treatment of fungal and bacterial infections. Finally, other applications will be envisaged such as the purification of physiological fluids. The project, which will consist of a systematic study of the relation between these properties and both the composition and structure of the hybrid solids, will be assisted by a strong modelling effort including top of the art computational methods (QSAR and QSPKR). This highly impact project will be realised by assembling experienced researchers in multidisplinary areas including materials science, biology and modelling. It will involve P. Horcajada (Institut Lavoisier), whose background in pharmaceutical science will fit with my experience in inorganic chemistry and G. Maurin (Institut Gerhardt, Montpellier) expert in computational chemistry.

This project will focus on the use of nanoporous metal organic frameworks (Fe, Zn, Ti) for bioapplications. These systems are exciting porous solids, built up from inorganic clusters and polycarboxylates. This results in open-framework solids with different pore shapes and dimensions, and applications such as catalysis, separation and storage of gases. I have recently initiated the synthesis of new trivalent transition metal carboxylates. Among them, the metal carboxylates MIL-100 and MIL-101 (MIL: Materials of Institut Lavoisier) are spectacular solids with giant pores (25-34 Å), accessible metal sites and huge surface areas (3100-5900 m2.g-1). Recently, it was shown that these solids could be used for drug delivery with a loading of 1.4 g of Ibuprofen per gram of MIL-101 solid and a total release in six days. This project will concentrate on the implication of MOFs for drug release and other bioapplications. Whereas research on drug delivery is currently focused either on the use of bio-compatible polymers or mesoporous materials, our method will combine advantages of both routes including a high loading and a slow release of therapeutic molecules. A second application will use solids with accessible metal sites to coordinate NO for its controlled delivery. This would provide exogenous NO for prophylactic and therapeutic processes, anti-thrombogenic medical devices, improved dressings for wounds and ulcers, and the treatment of fungal and bacterial infections. Finally, other applications will be envisaged such as the purification of physiological fluids. The project, which will consist of a systematic study of the relation between these properties and both the composition and structure of the hybrid solids, will be assisted by a strong modelling effort including top of the art computational methods (QSAR and QSPKR). This highly impact project will be realised by assembling experienced researchers in multidisplinary areas including materials science, biology and modelling. It will involve P. Horcajada (Institut Lavoisier), whose background in pharmaceutical science will fit with my experience in inorganic chemistry and G. Maurin (Institut Gerhardt, Montpellier) expert in computational chemistry.

SummaryCell motility is a fascinating dynamic process crucial for a wide variety of biological phenomena including defense against injury or infection, embryogenesis and cancer metastasis. A spatially extended, self-organized, mechanochemical machine consisting of numerous actin polymers, accessory proteins and molecular motors drives this process. This impressive assembly self-organizes over several orders of magnitude in both the temporal and spatial domains bridging from the fast dynamics of individual molecular-sized building blocks to the persistent motion of whole cells over minutes and hours. The molecular players involved in the process and the basic biochemical mechanisms are largely known. However, the principles governing the assembly of the motility apparatus, which involve an intricate interplay between biophysical processes and biochemical reactions, are still poorly understood. The proposed research is focused on investigating the biophysical aspects of the self-organization processes underlying cell motility and trying to adapt these processes to instill motility in artificial cells. Important biophysical characteristics of moving cells such as the intracellular fluid flow and membrane tension will be measured and their effect on the motility process will be examined, using fish epithelial keratocytes as a model system. The dynamics of the system will be further investigated by quantitatively analyzing the morphological and kinematic variation displayed by a population of cells and by an individual cell through time. Such measurements will feed into and direct the development of quantitative theoretical models. In parallel, I will work toward the development of a synthetic physical model system for cell motility by encapsulating the actin machinery in a cell-sized compartment. This synthetic system will allow cell motility to be studied in a simplified and controlled environment, detached from the complexity of the living cell.

Cell motility is a fascinating dynamic process crucial for a wide variety of biological phenomena including defense against injury or infection, embryogenesis and cancer metastasis. A spatially extended, self-organized, mechanochemical machine consisting of numerous actin polymers, accessory proteins and molecular motors drives this process. This impressive assembly self-organizes over several orders of magnitude in both the temporal and spatial domains bridging from the fast dynamics of individual molecular-sized building blocks to the persistent motion of whole cells over minutes and hours. The molecular players involved in the process and the basic biochemical mechanisms are largely known. However, the principles governing the assembly of the motility apparatus, which involve an intricate interplay between biophysical processes and biochemical reactions, are still poorly understood. The proposed research is focused on investigating the biophysical aspects of the self-organization processes underlying cell motility and trying to adapt these processes to instill motility in artificial cells. Important biophysical characteristics of moving cells such as the intracellular fluid flow and membrane tension will be measured and their effect on the motility process will be examined, using fish epithelial keratocytes as a model system. The dynamics of the system will be further investigated by quantitatively analyzing the morphological and kinematic variation displayed by a population of cells and by an individual cell through time. Such measurements will feed into and direct the development of quantitative theoretical models. In parallel, I will work toward the development of a synthetic physical model system for cell motility by encapsulating the actin machinery in a cell-sized compartment. This synthetic system will allow cell motility to be studied in a simplified and controlled environment, detached from the complexity of the living cell.

Max ERC Funding

900 000 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymBRAINPLASTICITY

ProjectIn vivo imaging of functional plasticity in the mammalian brain

Researcher (PI)Adi Mizrahi

Host Institution (HI)THE HEBREW UNIVERSITY OF JERUSALEM

Call DetailsStarting Grant (StG), LS4, ERC-2007-StG

Summary"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

Max ERC Funding

1 750 000 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymCANCERSTEM

ProjectStem cells in epithelial cancer initiation and growth

Researcher (PI)Cédric Blanpain

Host Institution (HI)UNIVERSITE LIBRE DE BRUXELLES

Call DetailsStarting Grant (StG), LS6, ERC-2007-StG

SummaryCancer is the result of a multi-step process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult stem cells (SCs) might be the initial target cells as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells characteristics of SC with high self-renewal capacities and the ability to reform the parental tumor upon transplantation. However, whether the initial oncogenic mutations arise in normal stem cells or in more differentiated cells that re-acquire stem cell-like properties remains to be determined. The demonstration that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. In most epithelia from which cancers naturally arise, such tools are not yet available. We have recently developed novel methods to specifically mark and isolate multipotent epidermal slow-cycling SCs, making it now possible to determine the role of SC during epithelial cancer formation. In this project, we will use mice epidermis as a model to define the role of SC in epithelial cancer initiation and growth. Specifically, we will determine whether epithelial SCs are the initial target cells of oncogenic mutations during skin cancer formation, whether oncogenic mutations lead preferentially to skin cancer when they arise in SC rather than in more committed cells and whether cancer stem cells contribute to epithelial tumor growth and relapse after therapy.

Cancer is the result of a multi-step process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult stem cells (SCs) might be the initial target cells as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells characteristics of SC with high self-renewal capacities and the ability to reform the parental tumor upon transplantation. However, whether the initial oncogenic mutations arise in normal stem cells or in more differentiated cells that re-acquire stem cell-like properties remains to be determined. The demonstration that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. In most epithelia from which cancers naturally arise, such tools are not yet available. We have recently developed novel methods to specifically mark and isolate multipotent epidermal slow-cycling SCs, making it now possible to determine the role of SC during epithelial cancer formation. In this project, we will use mice epidermis as a model to define the role of SC in epithelial cancer initiation and growth. Specifically, we will determine whether epithelial SCs are the initial target cells of oncogenic mutations during skin cancer formation, whether oncogenic mutations lead preferentially to skin cancer when they arise in SC rather than in more committed cells and whether cancer stem cells contribute to epithelial tumor growth and relapse after therapy.